Immune adjuvant for cancer

Abstract

The present invention relates to a medicament for treating cancer or infectious disease, the medicament comprising an immune checkpoint blockade and an adjuvant composition. More specifically, the present invention relates to a medicament for cancer or infectious diseases, wherein an anti-PD-1 antibody or an anti-PD-L1 antibody is used in combination with a nucleic acid adjuvant composed of a double-stranded RNA and a single-stranded ODN.

The invention claimed is: 
     
       1. A method for treating cancer or infectious disease, comprising administering an immune checkpoint blockade and an adjuvant composition to a patient in need thereof,
 wherein the immune checkpoint blockade comprises an anti-PD-1 antibody or an anti-PD-L1 antibody, 
 the adjuvant composition comprises a nucleic acid adjuvant comprising (i) a double-stranded RNA having a TLR3 activation ability, and (ii) a single-stranded oligodeoxynucleotide (single-stranded ODN) that is delivered to a dendritic cell endosome, wherein the double-stranded RNA has a nucleotide sequence comprising a sequence of continuous 40 or more bases of a nucleotide sequence represented by SEQ ID NO:1 and having a total length of 100 to 160 bases in length, and the single-stranded ODN consists of a sequence of a CpG ODN where CpG is replaced with GpC, TpC, or CpC, or a partial sequence thereof having 15 or more bases in length, 
 wherein the immune checkpoint blockade and the adjuvant are the sole active agents administered and results in activation of TLR3 to endosomes and/or induce tumor-specific CTLs to cause the tumor-specific CTLs to invade tumors, leading to tumor regression. 
 
     
     
       2. The method according to  claim 1 , wherein the immune checkpoint blockade and the adjuvant composition are separately administered. 
     
     
       3. The method according to  claim 1 , wherein the immune checkpoint blockade and the adjuvant composition are simultaneously administered. 
     
     
       4. The method according to  claim 1 , wherein the immune checkpoint blockade and the adjuvant composition are sequentially administered. 
     
     
       5. The method according to  claim 1 , wherein the adjuvant composition comprises an antigen molecule selected from the group consisting of bacterial antigen, viral antigens, and cancer antigen. 
     
     
       6. The method according to  claim 1 , wherein the nucleic acid adjuvant comprises a nucleic acid having a non-phosphorylated end. 
     
     
       7. The method according to  claim 1 , wherein the double-stranded RNA is a nucleic acid having a nucleotide sequence represented by one of SEQ ID NOs: 2 to 11, a nucleic acid having a nucleotide sequence having continuous 100 or more bases thereof. 
     
     
       8. The method according to  claim 1 , wherein the double-stranded RNA is a nucleic acid having a nucleotide sequence represented by SEQ ID NO: 11, a nucleic acid having a nucleotide sequence having continuous 100 or more bases thereof. 
     
     
       9. The method according to  claim 1 , wherein the single-stranded ODN is a nucleic acid consisting of a nucleotide sequence represented by one of SEQ ID NOs: 19 to 39 or a partial sequence thereof having 5 or more bases in length. 
     
     
       10. The method according to  claim 1 , wherein the single-stranded ODN is a nucleic acid consisting of a nucleotide sequence represented by one of SEQ ID NOs: 19 to 24 or a partial sequence thereof having 5 or more bases. 
     
     
       11. The method according to  claim 1 , wherein the single-stranded ODN has 15 to 28 bases in length. 
     
     
       12. The method according to  claim 1 , wherein the single-stranded ODN comprises a nucleotide modified with phosphorothioate. 
     
     
       13. The method according to  claim 1 , wherein the nucleic acid adjuvant is a nucleic acid comprising a sense strand represented by SEQ ID NO: 40 and an antisense strand represented by SEQ ID NO: 41, a nucleic acid comprising a sense strand represented by SEQ ID NO: 42 and an antisense strand represented by SEQ ID NO: 43. 
     
     
       14. The method according to  claim 1 , wherein the nucleic acid adjuvant comprises:
 1) a sense strand represented by SEQ ID NO: 40 and an antisense strand represented by SEQ ID NO: 41; 
 2) a sense strand represented by SEQ ID NO: 42 and an antisense strand represented by SEQ ID NO: 43; 
 3) a sense strand represented by SEQ ID NO: 44 and an antisense strand represented by SEQ ID NO: 45, or 4) a sense strand represented by SEQ ID NO: 46 and an antisense strand represented by SEQ ID NO: 47. 
 
     
     
       15. The method according to  claim 1 , wherein the cancer is a tumor that is not treated with the anti-PD-L1 antibody alone. 
     
     
       16. The method according to  claim 1 , wherein the cancer is metastatic cancer expressing PD-L1. 
     
     
       17. The method according to  claim 1 , wherein the double-stranded RNA has a total length of 110 to 150 bases.